CLN2 disease

CLN2 disease is a rare, inherited neurodegenerative disorder that causes progressive decline in motor skills, language, and cognition, leading to early death. Symptoms typically begin between ages 2 and 4 with seizures, ataxia (difficulty coordinating movements), and vision loss, followed by developmental regression, dementia, and muscle twitches (myoclonus). The disease is caused by mutations in the TPP1 gene, resulting in a deficiency of the TPP1 enzyme and the accumulation of proteins in brain cells. 

CLN2 disease symptoms typically appear between ages 2 and 4 and include recurrent seizures, difficulty with coordinated movement (ataxia), muscle twitches (myoclonus), and vision loss. Other signs include developmental regression, speech and language problems, behavioral issues, and the loss of previously acquired skills. The condition is a form of Batten disease that rapidly progresses, often leading to a complete loss of motor and language skills by age 6 and a shortened lifespan. 

CLN2 disease is caused by mutations in the CLN2 gene, which result in a deficiency of the tripeptidyl peptidase 1 (TPP1) enzyme. This deficiency prevents the proper breakdown of proteins and lipids, leading to their accumulation in lysosomes, particularly in nerve cells. This accumulation damages and eventually leads to the death of nerve cells, causing the progressive symptoms of the disease. The condition is inherited in an autosomal recessive manner, meaning a child must inherit two copies of the mutated gene, one from each parent, to have the disease. 

CLN2 disease, a rare genetic disorder, cannot be prevented in those who are genetically predisposed; however, it can be managed through genetic counseling and testing for at-risk families and has specific treatments like enzyme replacement therapy to slow its progression. Early diagnosis is crucial for effective management, and treatments focus on slowing the disease’s advancement and managing symptoms to improve quality of life. 

The diagnosis of CLN2 disease is confirmed through a combination of clinical signs and laboratory tests, including deficient tripeptidylpeptidase 1 (TPP1) enzyme activity and the identification of two pathogenic mutations in the CLN2/TPP1 gene. When clinical suspicion is high, a doctor will typically order both enzymatic and molecular tests to make a definitive diagnosis, with a deficient TPP1 enzyme activity and mutations in both CLN2 gene alleles being the gold standard. 

The prognosis for CLN2 disease without treatment is poor, leading to a fatal outcome, often by the late teens. Symptoms like seizures, loss of motor and language skills, and dementia progress rapidly. Enzyme replacement therapy (ERT) with cerliponase alfa (Brineura) can significantly slow the progression of neurological symptoms and extend life, but does not prevent blindness. 

The only FDA-approved treatment for CLN2 disease is cerliponase alfa (Brineura®), an enzyme replacement therapy that slows the progression of the disease by delivering the missing TPP1 enzyme directly to the brain. This treatment is delivered via a specific and regular infusion into the fluid surrounding the brain, which helps to slow the loss of motor and language skills, but it does not reverse existing damage or cure the disease. In addition to the enzyme therapy, other management strategies include medication for seizures, physical and occupational therapy, and nutritional support for patients with CLN2.